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The enteric nervous system (ENS) is a neural network referred to as "the brain in the gut" because of its similarities to the central nervous system (CNS). The ENS consists of numerous types of neurons and glial cells distributed in two intramuscular plexuses that span the length of the intestine and control coordinated smooth muscle contractile activity and other intestinal functions. It is well-established that reciprocal communication exists between the brain and the gastrointestinal tract. Although the ENS can function independently, it is connected to the CNS through the afferent and efferent pathways of the parasympathetic and sympathetic nervous systems. In addition to regulating ENS function by the CNS, these connections are likely to be critically involved in the pathophysiology of Parkinson's disease (PD). PD is a common neurodegenerative disorder that presents with non-motor and motor symptoms. Surprisingly, ENS lesions have been shown to occur very early in the disease, even before CNS involvement. This has led to the postulation that the ENS may be central to the pathophysiology of PD. Autopsy studies have shown that α-synuclein (αS) aggregates in PD patients are found both in the substantia nigra (SN) and the ENS. Therefore, it has been hypothesized that the pathological process leading to PD may initially occur in the ENS years before the appearance of motor features. This process induces misfolding and aggregation of αS in specific subtypes of neurons in the CNS. Finally, it spreads retrogradely in the CNS through preganglionic vagal fibers to the dorsal motor nucleus of this nerve and to other central nervous structures. In addition to the presumed role in the spread of the disease process, it has also been suggested that pathological changes in the ENS might be involved in the gastrointestinal dysfunction frequently seen in Pd patients. Starting from the evidence in animal models and using a translational point of view, in this review, we aim to summarize the role of the ENS in the pathogenesis of PD and how this system could be modulated for a novel therapeutic approach. While acknowledging the presumed role of the microbiome in the gut-brain axis, we will shift the focus from this point of view to focus more on the neurons of the ENS.

Word clustering (i.e., the ability to reproduce the same word pairs in consecutive recall trials of an unrelated word list) has been extensively investigated as a proxy of subjective organization (SO) of memorandum. In healthy subjects and in groups of brain-damaged patients, the rate of SO generally predicts accuracy of word list recall. This study aimed at evaluating SO in the performance of patients with Parkinson's disease (PD) on a word list recall task in order to investigate the basic mechanisms of episodic memory impairment that are frequently observed in these patients. For this purpose, 56 PD patients, who were stratified according to the presence and quality of mild cognitive impairment (MCI), and a group of healthy controls (HCs) were administered a word list task and an extensive battery of neuropsychological tests. Results showed that recall accuracy on the word list task progressively decreased passing from HC to PD patients without cognitive impairment, to patients with single-domain dysexecutive MCI and to patients with multiple-domain dysexecutive and amnesic MCI. Conversely, only the latter PD group showed a lower SO score than that achieved by the other groups. In the overall PD group, correlational and regression analyses demonstrated that SO scores and a composite score of executive functions were not reciprocally related, but both provided an independent and significant contribution to the prediction of word list recall accuracy. These data are discussed in terms of the contribution of executive functions and hippocampal storage processes to the onset of memory impairment in PD.

The harmonic structure of walking relies on an irrational number called the golden ratio (ϕ): in healthy subjects, it coincides with the stride-to-stance ratio, and it is associated with a smooth gait modality. This smoothness is lost in people with Parkinson&rsquo, s disease (PD), due to deficiencies in the execution of movements. However, external auditory cues seem to facilitate movement, by enabling the timing of muscle activation, and helping in initiating and modulating motor output. Based on a harmonic fractal structure of gait, can the administration of an auditory cue based on individual&rsquo, s ϕ-rhythm improve, in acute, gait patterns in people with PD? A total of 20 participants (16 males, age 70.9 &plusmn, 8.4 years, Hoehn and Yahr stage-II) were assessed through stereophotogrammetry: gait spatio-temporal parameters, and stride-to-stance ratio were computed before, during, and after the ϕ-rhythm administration. Results show improvements in terms of stride length (p = 0.018), walking speed (p = 0.014), and toe clearance (p = 0.013) when comparing gait patterns before and after the stimulus. Furthermore, the stride-to-stance ratio seems to correlate with almost all spatio-temporal parameters, but it shows the main changes in the before&ndash, during rhythm comparison. In conclusion, ϕ-rhythm seems an effective cue able to compensate for defective internal rhythm of the basal ganglia in PD.

The aim of this study was to investigate the effects of Equistasi&reg, a wearable device, on the relationship between muscular activity and postural control changes in a sample of 25 Parkinson&rsquo, s disease (PD) subjects. Gait analysis was carried out through a six-cameras stereophotogrammetric system synchronized with two force plates, an eight-channel surface electromyographic system, recording the activity of four muscles bilaterally: Rectus femoris, tibialis anterior (TA), biceps femoris, and gastrocnemius lateralis (GL). The peak of the envelope (PoE) and its occurrence within the gait cycle (position of the peak of the envelope, PPoE) were calculated. Frequency-domain posturographic parameters were extracted while standing still on a force plate in eyes open and closed conditions for 60 s. After the treatment with Equistasi&reg, the mid-low (0.5&ndash, 0.75) Hz and mid-high (0.75&ndash, 1 Hz) components associated with the vestibular and somatosensory systems, PoE and PPoE, displayed a shift toward the values registered on the controls. Furthermore, a correlation was found between changes in proprioception (power spectrum frequencies during the Romberg Test) and the activity of GL, BF (PoE), and TA (PPoE). Results of this study could provide a quantitative estimation of the effects of a neurorehabilitation device on the peripheral and central nervous system in PD.

Background: The containment measures taken by Italian government authorities during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic caused the interruption of neurological activities of outpatient clinics. Vulnerable patients, as Parkinson's disease (PD) and dystonic patients with deep brain stimulation (DBS), may have an increased risk of chronic stress related to social restriction measures and may show a potential worsening of motor and psychiatric symptoms.Methods: This cross-sectional multicenter study was carried out during the SARS-CoV-2 pandemic and was based on a structured survey administered during a telephone call. The questionnaire was designed to gather motor and/or psychiatric effects of the lockdown and coronavirus disease 2019 (COVID-19) epidemiologic information in PD and dystonic patients with a functioning DBS implant.Results: One hundred four patients were included in the study, 90 affected by PD and 14 by dystonia. Forty-nine patients reported a subjective perception of worsening of global neurological symptoms (motor and/or psychiatric) related to the containment measures. In the multivariate analysis, having problems with the DBS device was the only independent predictor of motor worsening [odds ratio (OR) = 3.10 (1.22–7.91), p = 0.018]. Independent predictors of psychiatric worsening were instrumental activities of daily living (IADL) score [OR = 0.78 (0.64–0.95), p = 0.012] and problems with DBS [OR = 5.69 (1.95–16.62), p = 0.001]. Only one patient underwent nasopharyngeal swabs, both negative, and no patient received a diagnosis of COVID-19.Conclusions: Lockdown restriction measures were associated with subjective worsening of motor and psychiatric symptoms in PD and dystonic patients treated with DBS, and they may have exacerbated the burden of neurological disease and increased the chronic stress related to the DBS management.

The aim of this study was to investigate the effects of Equistasi®, a wearable device, on the relationship between muscular activity and postural control changes in a sample of 25 Parkinson’s disease (PD) subjects. Gait analysis was carried out through a six-cameras stereophotogrammetric system synchronized with two force plates, an eight-channel surface electromyographic system, recording the activity of four muscles bilaterally: Rectus femoris, tibialis anterior (TA), biceps femoris, and gastrocnemius lateralis (GL). The peak of the envelope (PoE) and its occurrence within the gait cycle (position of the peak of the envelope, PPoE) were calculated. Frequency-domain posturographic parameters were extracted while standing still on a force plate in eyes open and closed conditions for 60 s. After the treatment with Equistasi®, the mid-low (0.5–0.75) Hz and mid-high (0.75–1 Hz) components associated with the vestibular and somatosensory systems, PoE and PPoE, displayed a shift toward the values registered on the controls. Furthermore, a correlation was found between changes in proprioception (power spectrum frequencies during the Romberg Test) and the activity of GL, BF (PoE), and TA (PPoE). Results of this study could provide a quantitative estimation of the effects of a neurorehabilitation device on the peripheral and central nervous system in PD.

Axial disorders, including postural deformities, postural instability, and gait disturbances, are among the most disabling symptoms of Parkinson's disease (PD). Equistasi®, a wearable proprioceptive stabilizer device, has been proposed as neurological rehabilitative device for this set of symptoms. To investigate the effects of the device on gait and balance, 24 participants affected by PD were enrolled in this crossover double-dummy, randomized, controlled study. Subjects were assessed four times before and after 8 weeks treatment with either active or placebo device; one-month wash-out was taken between treatments, in a 20-week timeframe. Gait analysis and instrumented Romberg test were performed with the aid of a sterofotogrammetric system and two force plates. Joint kinematics, spatiotemporal parameters of gait and center of pressure parameters were extracted. Paired T-test (p 0.05) was adopted after evidence of normality to compare the variables across different acquisition sessions; Wilcoxon was adopted for non-normal distributions. Before and after the treatment with the active device, statistically significant improvements were observed in trunk flexion extension and in the ankle dorsi-plantarflexion. Regarding balance assessment, significant improvements were reported at the frequencies corresponding to vestibular system. These findings may open new possibilities on PD's rehabilitative interventions. Research question, tailored design of the study, experimental acquisition overview, main findings, and conclusions.

Background: Subthalamic deep brain stimulation (STN-DBS) effects may decrease with Parkinson’s disease (PD) progression. There is no indication if, when, and how to consider the interruption of DBS treatment in late-stage PD. The objective of the current study was to investigate the percentage of “poor stimulation responders” among late-stage PD patients for elaborating an algorithm to decide whether and when DBS discontinuation may be considered. Methods: Late-stage PD patients (Hoehn Yahr stage ≥4 and Schwab and England Scale

Apathy is frequently reported in individuals with Parkinson's disease (PD) and is hypothesized to be associated with frontal-striatal related cognitive functions. Available data, however, do not provide univocal results. Moreover, this relationship has been poorly investigated in PD patients with mild cognitive impairment (MCI). This study was aimed at investigating the association between severity of apathy of PD patients and their performance on neuropsychological tests investigating executive abilities. Individuals with PD (i.e., with and without MCI) and healthy controls (HCs) were administered a neuropsychological test battery that investigated episodic memory, language, short-term memory and attention, visual-spatial abilities and executive functions. Subjects were also administered additional neuropsychological tests to evaluate the different executive subcomponents (i.e., planning/abstract reasoning, self-monitoring/response inhibition, working memory, shifting and fluency). The Apathy Evaluation Scale (AES) was administered to assess apathy severity. Linear regression analyses were applied to the data; results showed that in the PD group with MCI, the best cognitive factor associated to the AES score was patients' scores on the executive tests and, in particular, their scores on tests examining planning/abstract reasoning. By contrast, in the PD group without MCI, the cognitive performance was not significantly associated to apathy severity. Findings of the study document a specific association between reduced efficiency of the executive system and apathy severity in individuals with PD and MCI. This association indirectly supports the hypothesis of a relationship between motivational disorders and dysregulation of the activity of the frontal-striatal networks in PD patients.

The assessment of waveform similarity is a crucial issue in gait analysis for the comparison of electromyography (EMG) and kinematic patterns with reference data. A typical scenario is in fact the comparison of a patient’s EMG pattern with a relevant physiological pattern. Many methods have been proposed for a quantitative comparison of the two patterns, suggesting the absence of a gold standard. A recently proposed method for comparing kinematic patterns is the linear fit method (LFM). This study aims at testing the applicability of this method on data of EMG. The validity of LFM was tested in terms of appropriateness, sensitivity, specificity, and reliability, by comparing 20 EMG pathological gait patterns (obtained by a group of patients with Parkinson’s Disease) and 20 EMG physiological gait patterns (obtained by healthy subjects). When gastrocnemious and tibialis anterior EMG activity was analyzed, the appropriateness of LFM in discriminating pathological patterns resulted of 97.5%, with a sensitivity of 95% and a specificity of 100%. The reliability was good for 2 out of 3 parameters in each group of subjects. The LFM resulted a simple method suitable for analysing the waveform similarity in gait EMG clinical analysis.

Objective: The object of the study was to evaluate the efficacy of Proprioceptive Focal Stimulation on Gait in middle—advanced Parkinson (PD) patients by a crossover, randomized, double Blind double dummy study using Equistasi®, a nano-technological device of the dimension of a plaster which generates High Frequency Vibration (FV).Background: The efficacy of Gait Analysis (GA) on evaluating gait modification on Parkinson's disease (PD) Patients is already well-known. Therefore, GA was recorded in a group of PD patients using Equistasi® device and its placebo.Methods: Forty PD patients on optimal therapy were enrolled in the study. Patients were randomly assigned to receive active or sham stimulation for 8 weeks and, following a wash-out period, switched to an additional 8-week period with the reverse intervention. GA was performed at baseline and at the end of both 8-weeks treatment periods Clinical state was monitored by MDUPDRS part III.Results: Active stimulation induced a significant improvement in Mean Velocity (Velocity), Stride Length (SL), Stance (STA), and Double Support (DST) percentage, both in left and right stride. The ANOVA analysis using H&Y stage as a factor, showed that DST and MDUPDRS III scores improved significantly more in the more severely affected subjects.Conclusions: The findings obtained in this randomized controlled study show the efficacy of mechanical focal vibration, as stimulation of the proprioceptive system, in PD and encourage further investigation. The effect of the device on more severe patients may open a new possibility to identify the most appropriate candidate for the management of gait disturbances and postural instability with FV delivered with Equistasi®.

Background: For people with Parkinson&rsquo, s disease (PD), falls are a critical point. Focal vibration training (FVT) may represent a valid tool to improve postural performances and reduce the risk of falls. The aim of this study was to evaluate the efficacy of FVT to improve the postural stability in PD patients. Methods: Since October 2015, 55 consecutive PD patients have been selected (T0) for an approach including FVT associated with a rehabilitative protocol (RP), after eight weeks (T1), those patients showing a relevant improvement in the clinical rating scales ((Timed Up and Go (TUG), Tinetti, Unified Parkinson&rsquo, s disease rating scale (UPDRS) Part III, Berg Balance scale (BBS) and falls rate scale), continued with the FVT protocol (FVTRP group). The remaining patients continued with only the RP (RP group). In July 2018, we have extrapolated the data of the last clinical visit (T2) to observe any differences in the rate of falls. Results: The FVTRP group shows a decrement in the rate of falls from 2.1 to 1.25 (p 0.036) and a stability of the levodopa equivalent daily dosage (LEDD). The RP group shows an increment of LEDD and stability in falls. Conclusions: FVT has been confirmed as a valid tool to enhance the effect of the rehabilitation protocol aimed at postural training.

Background: For people with Parkinson’s disease (PD), falls are a critical point. Focal vibration training (FVT) may represent a valid tool to improve postural performances and reduce the risk of falls. The aim of this study was to evaluate the efficacy of FVT to improve the postural stability in PD patients. Methods: Since October 2015, 55 consecutive PD patients have been selected (T0) for an approach including FVT associated with a rehabilitative protocol (RP); after eight weeks (T1), those patients showing a relevant improvement in the clinical rating scales ((Timed Up and Go (TUG), Tinetti, Unified Parkinson’s disease rating scale (UPDRS) Part III, Berg Balance scale (BBS) and falls rate scale), continued with the FVT protocol (FVTRP group). The remaining patients continued with only the RP (RP group). In July 2018, we have extrapolated the data of the last clinical visit (T2) to observe any differences in the rate of falls. Results: The FVTRP group shows a decrement in the rate of falls from 2.1 to 1.25 (p 0.036) and a stability of the levodopa equivalent daily dosage (LEDD). The RP group shows an increment of LEDD and stability in falls. Conclusions: FVT has been confirmed as a valid tool to enhance the effect of the rehabilitation protocol aimed at postural training.

Background Recent evidence supports the hypothesis that rehabilitative strategies based on sensorimotor stimulation in the neurorehabilitation of Parkinson's disease (PD) may be useful to improve gait in PD patients. Aim We supposed that sensorimotor stimulation produces modulation of anticipatory postural adjustments (APAs) arising from the supplementary motor area (SMA). We aimed to investigate the clinical and neurophysiological effects of a blindfolded balance training (BBT). Design Randomized controlled trial. Setting Italian hospital. Population Sixteen PD patients. Methods The patients were randomized in two groups, one group treated with two-weeks BBT and one group treated with two-weeks of physical therapy (PT). We assessed gait parameters (swing, stance, double stance phase of cycle gait) and neurophysiological measurement (functional connectivity between SMA and motor area M1) before and after treatments. Results We found a decrease of stance and double stance phase and increase of swing phase respect to gait cycle, in BBT group compared to PT group, paralleled by a selective modulation in functional connectivity between M1 and SMA for BBT group. Conclusions Our findings support that BBT represents a complementary rehabilitative strategy, based on visual deprivation and proprioceptive perturbation in recovery of gait in PD patients, in short time window, likely involving vestibular system and its connections with motor areas. Clinical rehabilitation impact The use of vestibular system stimulation, involving SMA-M1 circuits, may be useful to improve gait control in PD patients.

Aim. Recent evidence suggested that the use of treadmill training may improve gait parameters. Visual deprivation could engage alternative sensory strategies to control dynamic equilibrium and stabilize gait based on vestibulospinal reflexes (VSR). We aimed to investigate the efficacy of a blindfolded balance training (BBT) in the improvement of stride phase percentage reliable gait parameters in patients with Parkinson’s Disease (PD) compared to patients treated with standard physical therapy (PT).Methods. Thirty PD patients were randomized in two groups of 15 patients, one group treated with BBT during two weeks and another group treated with standard PT during eight weeks. We evaluated gait parameters before and after BBT and PT interventions, in terms of double stance, swing, and stance phase percentage.Results. BBT induced an improvement of double stance phase as revealed (decreased percentage of double stance phase during the gait cycle) in comparison to PT. The other gait parameters swing and stance phase did not differ between the two groups.Discussion. These results support the introduction of complementary rehabilitative strategies based on sensory-motor stimulation in the traditional PD patient’s rehabilitation. Further studies are needed to investigate the neurophysiological circuits and mechanism underlying clinical and motor modifications.

Objective Verifying the validity and feasibility of the WOQ-19 as a useful tool in routine clinical practice and in management of patients. Methods 532 consecutive Parkinson's disease (PD) patients were recruited from 6 different neurological outpatient units, specialized in movement disorders, of central Italy. Inclusion criteria were diagnosis of PD and any current pharmacological treatment of PD while exclusion criteria were evident cognitive or depressive impairment, infusion with dopamine agonists or Duodopa, or Deep Brain Stimulation therapy. Patients were asked to complete the Italian version of WOQ-19 before the neurological visit. A medical form for the collection of demographic and clinical data of patients and for the evaluation of comprehensibility and usability the WOQ-19 was filled by the neurologist during the visit. Results Our data confirmed that WOQ-19 was able to identify WO in 69% of patients, a percentage similar to the recently reported in the Italian WOQ-19 validation study. Motor symptoms were more frequent than non-motor symptoms (80% vs. 20%). Patients who experienced WO had a higher age of PD onset, more severe disease, longer disease duration and were more likely to be female. Conclusions The WOQ-19 was understandable for the patient, easily administered and suitable for routine outpatient use. It could be also particularly useful in clinical practice in the early identification of non-motor symptoms, often under reported by patients and revealed only with clinical support.

It has been hypothesised that, in Parkinson’s disease (PD), dopamine might modulate spreading activation of lexical-semantic representations. We aimed to investigate this hypothesis in individuals with PD without dementia by assessing word frequency and typicality in verbal fluency tasks. We predicted that the average values of both of these parameters would be lower in PD patients with respect to healthy controls (HC). We administered letter-cued and category-cued fluency tasks to early PD patients in two experimental conditions: the tasks were administered both after 12–18 hours of dopaminergic stimulation withdrawal (“OFF” condition) and after the first daily dose of dopaminergic therapy (“ON” condition). HC were also given the two tasks in two conditions with the same intersession delay as PD patients but without taking drugs. Results showed that in both OFF and ON treatment conditions PD patients did not differ from HC in word frequency or typicality. Moreover, in the PD group, no significant difference was found between the experimental conditions. Our results show that semantic spreading was not altered in the PD sample examined; this suggests that in early PD the functioning of the semantic system is relatively independent from the activity of dopamine brain networks.

Background The effects of deep brain stimulation of the subthalamic nucleus (DBS-STN) and L-dopa (LD) on cortical activity in Parkinson's disease (PD) are poorly understood. Objectives By combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG) we explored the effects of STN-DBS, either alone or in combination with L-Dopa (LD), on TMS-evoked cortical activity in a sample of implanted PD patients. Methods PD patients were tested in three clinical conditions: i) LD therapy with STN-DBS turned on (ON/ON condition); ii) without LD therapy with STN-DBS turned on (OFF/ON condition); iii) without LD therapy with STN-DBS turned off (OFF/OFF condition). TMS pulses were delivered over left M1 while simultaneously acquiring EEG. Eight age-matched healthy volunteers (HC) were tested as a control group. Results STN-DBS enhanced early global TMS-evoked activity (∼45–80ms) and high-alpha TMS-evoked oscillations (11–13 Hz) as compared to OFF/OFF condition, independently from concomitant LD therapy. LD intake (ON/ON condition) produced a further increase of late TMS-evoked activity (∼80–130ms) and beta TMS-evoked oscillations (13–30 Hz), as compared to OFF/OFF and OFF/ON conditions, that normalized reactivity as compared to HC range of values. Conclusions Our data reveal that bilateral STN-DBS and LD therapy induce a modulation of specific cortical components and specific ranges of frequency. These findings demonstrate that STN-DBS and LD therapy may have synergistic effects on motor cortical activity.

Understanding the mental states of others entails a number of cognitive processes known as Theory of Mind (ToM). A relationship between ToM deficits and executive disorders has been hypothesized in individuals with Parkinson's disease (PD). The present study was aimed at investigating the effect of dysexecutive deficits on ToM abilities in PD patients without dementia. Participants included 30 PD patients and 30 healthy subjects (HC). PD patients were divided into two groups according to their executive test performance: patients with poor (dysexecutive group; n = 15) and normal (executively unimpaired group; n = 15) performance. All participants were administered faux pas recognition written stories. The dysexecutive PD patients performed less accurately than both HC and executively unimpaired PD individuals on all faux pas story questions (p < 0.05); the executively unimpaired PD group performed as accurately as the HC group on the ToM tasks. Results of the study clearly demonstrate that PD is not tout court associated with ToM impairments and that these may occur in PD patients as a function of the degree of their executive impairment. Our findings also indirectly confirm previous data on the role of the prefrontal regions in mediating ToM capacities.

STUDY OBJECTIVE: Sleep disorders are frequent non-motor symptoms in Parkinson disease (PD), probably due to multifactorial pathogeneses including disease progression, dopaminergic drugs, or concomitant illness. In recent years, the pedunculopontine tegmental (PPTg) nucleus has been considered a surgical target for deep brain stimulation (DBS) in advanced PD patients. As it is involved in controlling the sleep-wake cycle, we investigated the long-lasting effects of PPTg-DBS on the sleep of five PD patients implanted in both the PPTg and the subthalamic nucleus (STN) by rating two subjective clinical scales for sleep: the Parkinson's Disease Sleep Scale (PDSS), and the Epworth Sleepiness Scale (ESS). STUDY DESIGN: Sleep scales were administered a week before surgery (T0), three months after DBS (T1), and one year later (T2). In this study, STN-DBS was kept constantly in ON, and three different patterns of PPTg-DBS were investigated: STN-ON (PPTg switched off); PPTg-ON (PPTg stimulated 24 h/day); PPTg-cycle (PPTg stimulated only at night). RESULTS: In post-surgery follow-up, PD patients reported a marked improvement of sleep quality in all DBS conditions. In particular, stimulation of the PPTg nucleus produced not only a remarkable long-term improvement of nighttime sleep, but unlike STN-DBS, also produced significant amelioration of daytime sleepiness. CONCLUSION: Our study suggests that PPTg-DBS plays an important role in reorganizing regular sleep in PD patients.

Increasing evidence suggests that motor rehabilitation may delay Parkinson’s disease (PD) progression. Moreover, parallel treatments in animals up-regulate brain-derived neurotrophic factor (BDNF). Thus, we investigated the effect of a motor rehabilitation protocol on PD symptoms and BDNF serum levels. Motor rehabilitation training consisted of a cycle of 20 days/month of physiotherapy divided in 3 daily sessions. Clinical data were collected at the beginning, at the end, and at 90 days follow-up. BDNF serum levels were detected by ELISA at 0, 7, 14, 21, 30, and 90 days. The follow-up period had a duration of 60 days (T30–T90). The results showed that at the end of the treatment (day 30), an improvement in extrapyramidal signs (UPDRS III; UPDRS III – Gait and Balance items), motor (6 Minute Walking Test), and daily living activities (UPDRS II; PDQ-39) was observed. BDNF levels were increased at day 7 as compared with baseline. After that, no changes in BDNF were observed during the treatment and in the successive follow-up. This study demonstrates that motor rehabilitation training is able to ameliorate PD symptoms and to increase temporarily BDNF serum levels. The latter effect may potentially contribute to the therapeutic action.

Objective Recently, an intrinsic fractal harmonic structure was found underlying the rhythm of physiological walking, but it has not yet been investigated in subjects with a neurological disease. The aim of this study was to determine if and how this harmonic structure is altered in patients with Parkinson’s Disease. Methods Gait analysis of 70 patients with Parkinson’s Disease in pharmacological phase on was performed, the findings of which we compared with reference data of age-matched healthy subjects. Fifteen patients were retested after a washout period of 12 h. Results Alterations in all spatio-temporal gait parameters and gait indices with regard to symmetry, coordination, and harmony were noted, but after correction for multicollinearity bias, only the latter correlated significantly with Unified Parkinson’s Disease Rating Scale motor score (p = 0.001). The fractal gait structure underwent even more extensive alterations in pharmacological off phase (p Conclusions The intrinsic gait harmony was altered in patients with Parkinson’s Disease and significantly correlated to motor severity. It could be partially recovered by assumption of L-dopa. Significance Loss of harmony is a quantitatively assessable gait benchmark in Parkinson’s Disease. It seems to be dependent on dopaminergic but also on non-dopaminergic networks.

Background and purpose: To evaluate the effects of 25-Hz deep brain stimulation of the nucleus tegmenti pedunculopontini (PPTg) on brain metabolic activity. Methods: Six patients with Parkinson’s disease (PD) who had bilateral stereotactic implantation of PPTg at least 12 months prior to evaluation were included in our study. All underwent, in separate sessions, 18-FDG-PET in core assessment programme for intra-cerebral transplantation as well as motor evaluation [Unified Parkinson’s disease rating scale (UPDRS) – section III] and a battery of cognitive testing. Results: PPTg-ON (low bipolar contacts, 25 Hz) promoted a significant increase of glucose utilization in bilateral prefrontal areas including dorsolateral prefrontal cortex (DLPFC, BA9), orbito-frontal cortex (BA47), anterior cingulate (BA 25–32), superior frontal gyrus (BA 10) and supramarginal gyrus (BA40); a significant increase of uptake and consumption of FDG also occurred in the left ventral striatum, left subgyral (BA 46), right insula (BA 13) and right superior temporal gyrus (BA 22). PPTg-ON was associated with a significant decrease of glucose utilization in the left cerebellar anterior lobe (culmen) and right cerebellar posterior lobe (declive). In the same patients, PPTg-ON improved delayed recall (P

Combined deep brain stimulation of the subthalamic (STN) and pedunculopontine (PPN) nuclei has been recently proposed as surgical treatment of advanced Parkinson's disease. STN stimulation alone has been shown to provide selective improvement of the grammatical aspect of language. We studied five advanced Parkinson's disease patients who underwent combined deep brain stimulation (STN + PPN). Overall cognitive profile did not change. On the contrary, an interesting trend towards reduction of ungrammatical errors (particularly substitution of free and inflectional morphemes) was found when stimulating the STN, and also the PPN, when the STN was switched off. These findings replicate previous observations on the STN, and provide the rationale for further investigation of the role of the PPN in processing linguistic grammar.

The basal ganglia have been associated with temporal processing in ranges of milliseconds and seconds. However, results from PD patient studies are elusive. Time perception in these patients has been tested with different approaches including repetitive movement tasks (i.e. finger tapping) and cognitive tasks (i.e. time reproduction), and both abnormal and normal performances have been reported for different time intervals. Furthermore, when PD patients were required to learn two target durations in the same session when they were off medication, they overestimated the short duration and underestimated the long duration in the seconds range. This pattern of temporal accuracy was described as a "migration effect" and was interpreted as a dysfunctional representation of memory for time (Malapani, C., Rakitin, B. C., Levy, R., Meck, W. H., Deweer, B., Dubois, B., et al. (1998). Coupled temporal memories in Parkinson's disease: A dopamine-related dysfunction. Journal of Cognitive Neuroscience, 10, 316-331). Here, we controlled the emergence of similar behaviour also during millisecond time processing in PD patients. A time reproduction task was employed in which subjects were required to estimate intervals in millisecond (500 ms) and few second (2000 ms) ranges. In the first experiment, these intervals were tested in the same session to verify whether the migration effect was present also between time intervals in different millisecond and few second ranges. In a second experiment, they were not intermingled but were tested in two separate sessions to verify whether abnormalities depended on a selective perceptual deficit of the time intervals tested (i.e. millisecond or second ranges). All experiments were performed in both off and on therapy conditions. Our results demonstrated that PD patients showed no deficits in time estimation for time intervals in either the millisecond or few second range when the different time intervals were tested in separate sessions. This negative finding was obtained in both on and off conditions. However, when the different ranges were tested in the same session, we found that PD patients were impaired selectively for time intervals in the seconds range. Our data seem to indicate that time processing in PD patients for time intervals spanning up to 2 s is unimpaired and that abnormalities in such temporal scale may emerge only when patients have to deal with different durations, when timing involves further cognitive processes such as memory and attention. © 2007 Elsevier Ltd. All rights reserved.

Sixteen rigid-akinetic idiopathic Parkinson's disease patients (PD) and 13 healthy control subjects (controls) were included in this study.Gait analysis was performed using an optoelectronic system. The experimental design involved double evaluation of PD patients (before and after motor rehabilitation program) and a single evaluation of controls. ANOVA was performed in both groups for each gait variable (kinetic and kinematic) and for clinical conditions.Analysis of kinetic data highlighted a statistically significant difference for all gait variables studied between controls and PD patients either before, or in the same PD patients before and after the motor rehabilitation program. After the rehabilitation program, natural walking speed increased (p.000). The stance percentage was significantly decreased in the single support (p.000). After the rehabilitation program, the double support limb phase did not show a reduction in statistical significance. Kinematic data showed statistical differences between controls and PD patients in hip, knee and ankle joint angles, both before and after the motor rehabilitation program.Our results confirm that gait analysis is a valid tool for evaluating changes in PD patients' ability to walk and for quantifying the improvements gained through a motor rehabilitation program.

Objective. Prospective memory (PM), that is, the ability to keep in memory and carry out intentions in the future, is reported to be impaired in individuals with Parkinson's disease (PD). PM failure may be also associated with reduced daily living functioning in these patients. Little is known, however, about the relationship between mild cognitive impairment (MCI) and time-based PM functioning in PD patients and the possible impact of PM deficits on patients' autonomy in daily living. Here we aimed to investigate whether MCI associated with PD affects time-based PM. We also wished to determine whether PM impairment accounts for reduced autonomous management of medication in these patients. Method. The study included 48 PD patients with MCI, 33 PD patients without cognitive disorders (PDN) and 20 healthy controls. The time-based PM procedure required that subjects perform an action after a fixed time. The PM procedure was incorporated in the standard neuropsychological assessment. One score was computed for the ability to retrieve the intention (prospective component) and one for remembering the action to be executed (retrospective component). The Pill Questionnaire was administered to assess the ability to manage medication. Results. PD patients with MCI performed less accurately in the PM procedure than HC and tended to perform poorer than PDN. Moreover, in PD patients with MCI, accuracy on the prospective component of the PM task and performance on the Modified Card Sorting Test significantly predicted the ability to manage medication. Conclusions. Results document that reduced efficiency of time-based PM processes in PD is specifically related to the presence of MCI. The same data indicate that PM weakness may be associated with impaired daily living functioning and decreased autonomy.

Parkinson’s disease (PD) patients, besides motor dysfunctions, may also display mild cognitive deficits (MCI) which increase with disease progression. The neurotrophin brain-derived neurotrophic factor (BDNF) plays a role in the survival of dopaminergic neurons and in the regulation of synaptic connectivity. Moreover, the brain and peripheral level of this protein may be significantly reduced in PD patients. These data suggest that a cognitive rehabilitation protocol aimed at restoring cognitive deficits in PD patients may also involve changes in this neurotrophin. Thus, in this pilot study we evaluated the effect of a cognitive rehabilitation protocol focused on the training of executive functioning and measured BDNF serum levels in a group of PD patients with mild cognitive impairment, as compared to the effect of a placebo treatment (n = 7/8 group). The results showed that PD patients undergoing the cognitive rehabilitation, besides improving their cognitive performance as measured with the Zoo Map Test, also displayed increased serum BDNF levels as compared to the placebo group. These findings suggest that BDNF serum levels may represent a biomarker of the effects of cognitive rehabilitation in PD patients affected by MCI. However, the functional significance of this increase in PD as well as other neuropathological conditions remains to be determined.

Objective Prospective memory (PM) is the ability to keep in memory and realize future intentions. We aimed at investigating whether in Parkinson's disease (PD) PM deficits are related to mild cognitive impairment (MCI). Other aims were to investigate the cognitive abilities underlying PM performance, and the association between PM performance and measures of daily living functioning. Method The study included 15 PD patients with single domain MCI, 15 with multiple domain MCI, 17 PD patients without cognitive disorders (PDNC) and 25 healthy controls (HCs). All subjects were administered a PM procedure that included focal (PM cue is processed in the ongoing task) and nonfocal (PM cue is not processed in the ongoing task) conditions. PD patients were administered an extensive neuropsychological battery and scales to assess daily living abilities. Results PD patients with MCI (both single and multiple domains) showed lower accuracy on all PM conditions than both HC and PDNC patients. This was predicted by their scores on shifting indices. Conversely, PM accuracy of PDNC patients was comparable to HCs. Regression analyses revealed that PD patients' PM performance significantly predicted scores on daily living scales Conclusions: Results suggest that PM efficiency is not tout-court reduced in PD patients, but it specifically depends on the presence of MCI. Moreover, decreased executive functioning, but not episodic memory failure, accounts for a significant proportion of variance in PM performance. Finally, PM accuracy indices were found to be associated with measures of global daily living functioning and management of medication.

Introduction. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and of the pars interna of Globus Pallidus (GPi) is used to improve parkinsonian symptoms and attenuate levodopa-induced motor complications in Parkinson's disease (PD) (DBS for PD study group, 2001). It is still not clear what the best anatomic structures to stimulate are or what the physiologic effects of DBS are. Most of the studies regarding DBS for parkinsonian symptoms have been conducted in patients with STN implantation, and these studies reported significant improvement in motor function with a relatively low rate of complication. The large experience of ablative surgery associated with the DBS experience of some groups worldwide indicate that GPi is a possible and very promising target for the management of parkinsonian symptoms. Surgical procedures have become safer and it is now possible, in selected cases, to target both structures in the same patient by means of the stereotactic system, "3P Maranello" (CLS-SRL, Italy). Using this system we were able to evaluate the clinical effects of simultaneous stimulation of both STN and GPi as well as evaluate the effects of isolated stimulation of each target. As it is known that there is a high intersubject variability of DBS, it seems relevant to test all different combinations of DBS in the same patient. Methods. We assessed the effects of DBS in 13 cases of PD, immediately after (30 min) stimulation and during chronic stimulation (weeks or months). Patients fell into two groups. The first (n = 7) responded to both GPi and STN stimulation equally. The second group (n = 6) was preferentially stimulated with only one target (STN = 5, GPi = 1). Results. There was a good reduction in levodopa treatment following surgery. Most patients remained were chronically treated with bilateral stimulation of both targets. Conclusion. We conclude that DBS of STN and GPi was effective, with most patients treated chronically with both targets stimulated.

Although the effects of subthalamic nucleus stimulation on the control of motor symptoms in patients with Parkinson's disease have been demonstrated, to our knowledge there are no data on effects of this treatment on voiding. We evaluated differences in urodynamic findings in patients with Parkinson's disease during on and off subthalamic nucleus stimulation status.We evaluated 3 males and 2 females with Parkinson's disease. All patients had undergone surgical bilateral implantation of subthalamic nucleus electrodes 4 to 9 months before our observation. Urodynamic evaluation was performed during chronic subthalamic nucleus stimulation and 30 minutes after turning off the stimulators. Certain parameters were evaluated, including bladder compliance and capacity, first desire to void volume, bladder volume of appearance (reflex volume) and amplitude of detrusor hyperreflexic contractions, maximum flow, detrusor pressure at maximum flow and detrusor-sphincter coordination. Results were compared statistically.Statistically significant differences in urodynamic data obtained during on and off subthalamic nucleus stimulation status were noted. In particular bladder capacity and reflex volume were increased for on status (median 320 versus 130 ml., p = 0.043 and 250 versus 110, p = 0.043, respectively). The amplitude of detrusor hyperreflexic contractions was decreased for on status but the difference was not significant (median 23 versus 37 cm. H2O, p = 0.223). No differences were noted in the other urodynamic parameters considered during the filling and voiding phases.Our experience shows that subthalamic nucleus stimulation seems to be effective for decreasing detrusor hyperreflexia in Parkinson's disease cases. This finding confirms a role for basal ganglia in voiding control.

Question Deep brain stimulation (DBS) of the subthalamic nucleus (STN) represents an effective therapy in Parkinson’s disease (PD). The effects of STN-DBS on cortical reactivity are still poorly understood. By combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG), we explored the effects of STN-DBS either alone or in combination with levodopa (LD), on cortical activity evoked by TMS of the primary motor cortex (M1) in a sample of PD patients chronically treated with STN implantation. Methods Six advanced PD patients treated with STN-DBS were tested in three clinical conditions on distinct days: (i) on therapy/on DBS; (ii) off therapy/on DBS; (iii) off therapy/off DBS. In each condition, 80 single TMS pulses were delivered over left M1 while simultaneously acquiring EEG. We evaluated TMS-induced changes in the time domain and in the time/frequency domain. Results In the OFF/ON condition there was a significant increase of GMFP peaking at 60–70 ms (P2) compared to OFF/OFF condition. In ON/ON condition a significant increase of GMFP peaking at 60–70 ms (P2) and at 100 ms (P3) was observed compared to OFF/OFF condition. Time/frequency analysis showed a synchronization of activity in the 10–17 Hz range over central-posterior region within the P2 time window in the OFF/ON condition compared to OFF/OFF. The same analysis conducted on the P3 time window revealed a synchronization of activity in the 11–16 Hz range of frequency over central regions when comparing OFF/ON condition to ON/ON. Conclusions Our data reveal that bilateral STN-DBS induces a significant modulation of cortical global reactivity at early components. The association of LD therapy produces additional distinct modulation of later components. These findings could be related to cortical induced modulation of GABAergic intracortical activity.

This study investigated the effect of cognitive training aimed at improving shifting ability on Parkinson’s disease (PD) patients’ performance of prospective memory (PM) tasks. Using a double-blind protocol, 17 PD patients were randomly assigned to two experimental arms. In the first arm (n=9) shifting training was administered, and in the second (placebo) arm (n=8), language and respiratory exercises. Both treatments consisted of 12 sessions executed over 4 weeks. PM and shifting measures (i.e., Trail Making Test and Alternate Fluency Test) were administered at T0 (before treatment) and T1 (immediately after treatment). A mixed analysis of variance was applied to the data. To evaluate the effects of treatment, the key effect was the interaction between Group (experimental vs. placebo) and Time of Assessment (T0 vs. T1). This interaction was significant for the accuracy indices of the PM procedure (pp≤.05). Tukey’s HSD tests showed that in all cases passing from T0 to T1 performance significantly improved in the experimental group (in all cases p≤.02) but remained unchanged in the placebo group (all p consistently>.10). The performance change passing from T0 to T1 on the Alternate Fluency test and the PM procedure was significantly correlated (pJINS, 2014, 20, 1–10)

Background. Previous data suggest that (i) dopamine modulates the ability to implement nonroutine schemata and update operations (flexibility processes) and that (ii) dopamine-related improvement may be related to baseline dopamine levels in target pathways (inverted U-shaped hypothesis).Objective. To investigate above hypotheses in individuals with Parkinson's disease (PD).Methods. Twenty PD patients were administered tasks varying as to flexibility load in two treatment conditions: (i) “off” condition, about 18 hours after dopamine dose and (ii) “on” condition, after dopamine administration. PD patients were separated into two groups: low performers (i.e., performance on Digit Span Backward below the sample mean) and high performers (i.e., performance above the mean). Twenty healthy individuals performed the tasks in two sessions without taking drugs.Results. Passing from the “off” to the “on” state, only low performer PD patients significantly improved their performance on high-flexibility measures (interference condition of the Stroop test;P<0.05); no significant effect was found on low-flexibility tasks.Conclusions. These findings document that high-flexibility processes are sensitive to dopamine neuromodulation in the early phases of PD. This is in line with the hypothesis that striatal dopamine pathways, affected early by PD, are precociously implicated in the expression of cognitive disorders in these individuals.

The hypothesis has been advanced that memory disorders in individuals with Parkinson's disease (PD) are related to either retrieval or consolidation failure. However, the characteristics of the memory impairments of PD patients with amnestic mild cognitive impairment have not been clarified. This study was aimed at investigating whether memory deficits in PD patients with amnestic mild cognitive impairment (PDaMCI) are due to failure of retrieval or consolidation processes. Sixteen individuals with PDaMCI, 20 with amnestic mild cognitive impairment without PD (aMCINPD), and 20 healthy controls were recruited. Participants were administered the Free and Cued Selective Reminding Test. An index of cueing was computed for each subject to capture the advantage in retrieval of cued compared to free recall. Individuals with PDaMCI performed worse than healthy controls on the free recall (p0.10) task, and they performed better than aMCINPD subjects on both recall measures (p0.10) but it was significantly higher than that of the aMCINPD sample (p

In Parkinson's disease (PD) patients, internal globus pallidus (GPi) stimulation has been reported to produce good effects on abnormal involuntary movements (AIM); less improvement has been observed in extrapyramidal symptoms. We assessed the effect of monopolar dorsal (uppermost), ventral (lowest) and bipolar (uppermost vs. lowest) bilateral globus pallidus stimulation by quadripolar electrode on extrapyramidal symptoms and AIM induced by a dose of apomorphine. Six PD patients were studied in OFF therapy condition after surgery without stimulation (STIM OFF) and during stimulation (STIM ON) with the three different modalities. All patients were evaluated by the unified Parkinson's disease rating scale, section III (UPDRS) and by the AIM. Our results show that all three bilateral GPi stimulation modalities reduce the UPDRS score (between 49.7 and 31.5%), although the bipolar and lowest stimulation are the most effective. Similarly, bipolar and lowest stimulation were also the most effective in reducing the occurrence and intensity of the apomorphine-induced AIM. On the contrary, uppermost stimulation (UP ON) produced an AIM occurrence similar to that observed in the OFF stimulus condition. We suggest that bilateral GPi stimulation is an useful procedure to ameliorate extrapyramidal signs of advanced PD patients; however, it produces an antidyskinetic effect only if the ventral or the entire GPi is stimulated. On the contrary, the UP ON, most probably located in the external globus pallidus (GPe), does not modify the AIM occurrence.

Gait coordination was analyzed (four-camera 100 Hz ELITE system) in two groups of idiopathic Parkinson disease (PD) patients. Five patients underwent continuous infusion of apomorphine and were recorded in two different sessions (APO OFF and APO ON) in the same day. Three patients with a previous chronic electrode implantation in both internal globi pallidi (GPi) were recorded in the same experimental session with the electrodes on and off (STIM ON and STIM OFF). The orientation of both the trunk and the lower-limb segments was described with respect to the vertical in the sagittal plane. Lower-limb inter-segmental coordination was evaluated by analyzing the co-variation between thigh, shank, and foot elevation angles by means of orthogonal planar regression. At least 30 gait cycles per experimental condition were processed. We found that the trunk was bent forward in STIM OFF, whereas it was better aligned with the vertical in STIM ON in both PD groups. The legs never fully extended during the gait cycle in STIM OFF, whereas they extended before heel strike in STIM ON. The multisegmental coordination of the lower limb changed almost in parallel with the changes in trunk orientation. In STIM OFF, both the shape and the spatial orientation of the planar gait loops (thigh angle vs. shank angle vs. foot angle) differed from those of physiological locomotion, whereas in STIM ON the gait loop tended to resume features closer to the control. Switching the electrodes on and off in patients with GPi electrodes resulted in quasi-parallel changes of the trunk inclination and of the planar gait loop. The bulk of the data suggest that the basal-ganglia circuitry may be relevant in locomotion by providing an appropriate spatio-temporal framework for the control of posture and movement in a gravity-based body-centered frame of reference. Pallido-thalamic and/or pallido-mesencephalic pathways may influence the timing of the inter-segmental coordination for gait.

In nature, many physical and biological systems have structures showing harmonic properties. Some of them were found related to the irrational number φ known as the golden ratio that has important symmetric and harmonic properties. In this study, the spatiotemporal gait parameters of 25 healthy subjects were analyzed using a stereophotogrammetric system with 25 retroreflective markers located on their skin. The proportions of gait phases were compared with φ, the value of which is about 1.6180. The ratio between the entire gait cycle and stance phase resulted in 1.620 ± 0.058, that between stance and the swing phase was 1.629 ± 0.173, and that between swing and the double support phase was 1.684 ± 0.357. All these ratios did not differ significantly from each other (F = 0.870, P = 0.422, repeated measure analysis of variance) or from φ (P = 0.670, 0.820, 0.422, resp., t-tests). The repetitive gait phases of physiological walking were found in turn in repetitive proportions with each other, revealing an intrinsic harmonic structure. Harmony could be the key for facilitating the control of repetitive walking. Harmony is a powerful unifying factor between seemingly disparate fields of nature, including human gait.

The study was aimed at investigating the contribution of retrospective memory to prospective memory (PM) functioning in people with Parkinson's disease (PD). Twenty patients with PD without dementia and 20 normal controls were recruited. In the PM procedure, sequences of words were presented; in the inter-sequence delay, participants had to repeat sequence in the same or reverse order (ongoing task). At the occurrence of a target word, participants had to press a button on the keyboard (PM response). To evaluate the contribution of retrospective memory to PM performance, we manipulated the retrospective memory load of the target words (i.e., one vs. four words). The results show that patients with PD were poorer than controls in all PM conditions (p

Deep brain stimulation (DBS) of the subthalamic nucleus (STN), in Parkinson’s disease (PD) patients, is a well established therapeutic option, but its mechanisms of action are only partially known. In our previous study, the clinical transitions from OFF- to ON-state were not correlated with significant changes of GABA content inside GPi or substantia nigra reticulata. Here, biochemical effects of STN-DBS have been assessed in putamen (PUT), internal pallidus (GPi), and inside the antero-ventral thalamus (VA), the key station receiving pallidothalamic fibres. In ten advanced PD patients undergoing surgery, microdialysis samples were collected before and during STN-DBS. cGMP, an index of glutamatergic transmission, was measured in GPi and PUT by radioimmunoassay, whereas GABA from VA was measured by HPLC. During clinically effective STN-DBS, we found a significant decrease in GABA extracellular concentrations in VA (- 30%). Simultaneously, cGMP extracellular concentrations were enhanced in PUT (+200%) and GPi (+481%). These findings support a thalamic dis-inhibition, in turn re-establishing a more physiological corticostriatal transmission, as the source of motor improvement. They indirectly confirm the relevance of patterning (instead of mere changes of excitability) and suggest that a rigid interpretation of the standard model, at least when it indicates the hyperactive indirect pathway as key feature of hypokinetic signs, is unlikely to be correct. Finally, given the demonstration of a key role of VA in inducing clinical relief, locally administration of drugs modulating GABA transmission in thalamic nuclei could become an innovative therapeutic strategy.

At odd with traditional views, effective sub-thalamic nucleus (STN) deep brain stimulation (DBS), in Parkinson's disease (PD) patients, may increase the discharge rate of the substantia nigra pars reticulata and the internal globus pallidus (GPi), in combination with increased cyclic guanosine monophosphate (cGMP) levels. How these changes affect the basal ganglia (BG) output to the motor thalamus, the crucial structure conveying motor information to cortex, is critical. Here, we determined the extracellular GABA concentration in the ventral anterior nucleus (VA) during the first delivery of STN-DBS (n=10) or following levodopa (LD) (n=8). Both DBS and subdyskinetic LD reversibly reduced (−30%) VA GABA levels. A significant correlation occurred between clinical score and GABA concentration. By contrast, only STN-DBS increased GPi cGMP levels. Hence, STN-ON and MED-ON involve partially different action mechanisms but share a common target in the VA. These findings suggest that the standard BG circuitry, in PD, needs revision as relief from akinesia may take place, during DBS, even in absence of reduced GPi excitability. However, clinical amelioration requires fast change of thalamic GABA, confirming, in line with the old model, that VA is the core player in determining thalamo-cortical transmission.

Previous studies have demonstrated that non-demented Parkinson’s disease (PD) patients have a specific impairment of verb production compared with noun generation. One interpretation of this deficit suggested the influence of striato-frontal dysfunction on action-related verb processing. The aim of our study was to investigate cerebral changes after motor improvement due to dopaminergic medication on the neural circuitry supporting action representation in the brain as mediated by verb generation and motor imagery in PD patients. Functional magnetic resonance imaging on 8 PD patients in “ON” dopaminergic treatment state (DTS) and in “OFF” DTS was used to explore the brain activity during three different tasks: Object Naming (ObjN), Generation of Action Verbs (GenA) in which patients were asked to overtly say an action associated with a picture and mental simulation of action (MSoA) was investigated by asking subjects to mentally simulate an action related to a depicted object. The distribution of brain activities associated with these tasks whatever DTS was very similar to results of previous studies. The results showed that brain activity related to semantics of action is modified by dopaminergic treatment in PD patients. This cerebral reorganisation concerns mainly motor and premotor cortex suggesting an involvement of the putaminal motor loop according to the “motor” theory of verb processing.

In patients with Parkinson's disease, aberrant or excessive dopaminergic stimulation is commonly indicated as the trigger factor in unmasking impulse control disorders (ICDs) such as pathological gambling. We had the opportunity to follow a patient who experienced Parkinson's disease 7 years ago when he was using pramipexole and again, recently, when he was treated with levodopa (L-dopa) and low frequency stimulation of the nucleus of the pedunculopontine tegmentus (PPTg) but no dopamine agonists. The same patient had shown, when studied with fluorodeoxyglucose-positron emission tomography in the condition PPTg-ON, a peculiar increased activity in the left ventral striatum. This case report confirms that, in a predisposed personality, ICD may arise from the perturbation of endogenous pathways, which connect the brainstem to the basal ganglia.

One objective of modern neuroimaging is to identify markers that can aid in diagnosis, disease progression monitoring and long-term drug impact analysis. In this study, Parkinson-associated physiopathological modifications were characterized in six subcortical structures by simultaneously measuring quantitative magnetic resonance parameters sensitive to complementary tissue characteristics (i.e. volume atrophy, iron deposition and microstructural damage). Thirty patients with Parkinson's disease and 22 control subjects underwent 3-T magnetic resonance imaging with T₂*-weighted, whole-brain T₁-weighted and diffusion tensor imaging scans. The mean R₂* value, mean diffusivity and fractional anisotropy in the pallidum, putamen, caudate nucleus, thalamus, substantia nigra and red nucleus were compared between patients with Parkinson's disease and control subjects. Comparisons were also performed using voxel-based analysis of R₂*, mean diffusivity and fractional anisotropy maps to determine which subregion of the basal ganglia showed the greater difference for each parameter. Averages of each subregion were then used in a logistic regression analysis. Compared with control subjects, patients with Parkinson's disease displayed significantly higher R₂* values in the substantia nigra, lower fractional anisotropy values in the substantia nigra and thalamus, and higher mean diffusivity values in the thalamus. Voxel-based analyses confirmed these results and, in addition, showed a significant difference in the mean diffusivity in the striatum. The combination of three markers was sufficient to obtain a 95% global accuracy (area under the receiver operating characteristic curve) for discriminating patients with Parkinson's disease from controls. The markers comprising discriminating combinations were R₂* in the substantia nigra, fractional anisotropy in the substantia nigra and mean diffusivity in the putamen or caudate nucleus. Remarkably, the predictive markers involved the nigrostriatal structures that characterize Parkinson's physiopathology. Furthermore, highly discriminating combinations included markers from three different magnetic resonance parameters (R₂*, mean diffusivity and fractional anisotropy). These findings demonstrate that multimodal magnetic resonance imaging of subcortical grey matter structures is useful for the evaluation of Parkinson's disease and, possibly, of other subcortical pathologies.

Patients with Parkinson’s disease (PD) frequently display non-motor symptoms. In this study, we investigated intensity-dependent facial emotion recognition in patients with PD and healthy controls (HC), matched for age, gender, and education, and its relationship to individual cognitive domains. Seventy patients with PD and 70 HC were submitted to a clinical, neuropsychological, and psychopathological evaluation. Facial emotion recognition performance was assessed using the Penn Emotion Recognition Test (PERT). The patients with PD recognized fewer low- and high-intensity facial expressions of disgust than HC. This effect was selective, because their global ability to recognize emotions was intact. Both patients with PD and HC recognized high-intensity better than low-intensity emotions, except for disgust, which was recognized better at low intensity. In the patients with PD, overall facial emotion recognition and selective disgust recognition performances were related to deficits in many neuropsychological domains (verbal and visuo-spatial memory, attention, praxis, and verbal fluency). The ability to recognize emotions is a complex cognitive process requiring the integrity of several functions. Therefore, it is likely that structural or functional derangement of the discrete neural pathways involved in these cognitive functions in patients with PD makes it difficult for them to recognize emotions expressed by others. (JINS, 2010, 16, 867–876.)